The full therapeutic value of some pharmaceutical compounds (e.g., medications, drugs) may be difficult to realize due to off-setting unwanted or adverse effects (e.g., toxic effects). In some cases, one or more unwanted or adverse effects of a pharmaceutical may be so significant, that the agent cannot be used safely in humans using other formulations. In other cases, dosages may have to be limited to avoid an unwanted or adverse effect. In still other cases, the course of therapy may have to be shortened. In addition, exigent circumstances or life-threatening illnesses may compel patients to simply endure such unwanted or adverse effects to gain a pharmaceutical compound's benefits.
Ulcerative lesions of the gastrointestinal tract are one of the major side effects associated with the use of alcohol, non-steroidal anti-inflammatory drugs (NSAIDs) and gastric irritating drugs (e.g., antibiotics, adrenal corticoid steroids, anti-cancer drugs). Accumulation of neutrophils and/or oxygen free radicals and/or inhibition of prostaglandins may play a significant role in the mechanism of gastrointestinal lesions induced by ethanol, NSAIDS, and gastric irritating drugs.
Oral administration of high concentrations of ethanol (i.e., 75-100%) and/or oral administration of moderate concentrations of acidic ethanol may be extremely damaging to gastrointestinal epithelium (e.g., in rats). Such concentrations or combinations may be used to induce damage experimentally to investigate the efficacy of various gastrointestinal protective agents against the use of alcohol, short- or long-term NSAIDS, and/or gastric irritating drugs. Lower doses of ethanol (e.g., about 40% to about 50%) may be less toxic, particularly if administered in a non-acid medium. For example, exposure of the gastroduodenal mucosa to a 50% ethanol solution may cause only mild damage macroscopically to the glandular portion of the stomach. Similarly, exposure of the gastroduodenum to 150 mM HCl may cause no visible damage to the gastroduodenal mucosa. In contrast, administration of about 50% ethanol in 150 mM HCl may lead to severe macroscopic injury involving as much as 20% of the glandular mucosa. In fact, a solution of 50% ethanol in 150 mM HCl may be as severely damaging as absolute ethanol alone or 750 mM HCl alone. Thus relatively small amounts of HCl and a moderate concentration of ethanol have a synergistic effect that greatly exacerbates the gastroduodenal injury one would expect from the activity of these agents alone.
Ingestion of high concentrations of ethanol may result in hemorrhagic gastritis characterized by mucosal edema, subepithelial hemorrhages, cellular exfoliation and inflammatory cell infiltration. Hemorrhagic gastritis usually coexists with duodenal erosive lesions like edema and vacuole. Ingestion of moderate concentrations of ethanol may affect the mucosal barrier and histology. Morphologically, alcohol-induced gastroduodenal superficial injury may involve the inter-foveolar epithelium and gastroduodenal pits, and may heal rapidly by restitution. On the other hand, deeper lesions associated with ingestion of high concentrations of ethanol may involve intramucosal hemorrhage and vascular engorgement. As a consequence of damage to microvessels, leakage of inflammatory mediators may occur, and vasoconstriction of submucosal arteries may result in ischemia. Eventually, these events may lead to severe necrotic mucosal injury.
NSAIDs, which may include drugs with analgesic, antipyretic and/or anti-inflammatory effects, are widely used. Gastrointestinal toxicity may be observed as gastrointestinal mucosal damage like acute hemorrhagic erosions as well as small bowel and colon injury. Small intestinal damage may be observed as ulceration, perforation, and stricture, particularly following long term administration of NSAIDs. Patients receiving NSAIDs long-term may further display enteropathy including intestinal inflammation, acute blood loss, protein loss, and/or vitamin B12 or bile acid malabsorption. NSAIDs may also induce mucosal damage of the large intestine. Compromise of the colon may include de novo NSAID induced colitis, reactivation of quiescent colitis, and/or lower gastrointestinal bleeding from diverticular disease.